The risk of radiation pneumonitis limits both the dose of radiation that can be delivered as well as the volume of the thorax that can be treated. It appears that the dose of radiation, the amount of lung radiated, and the use of concurrent chemotherapy affect the risk of developing radiation pneumonitis.

Protons may be able to further reduce pneumonitis by decreasing the dose and volume of normal lung radiated. The present study is a retrospective single institution study examining rates of pneumonitis in patients treated with concurrent chemotherapy/photons as compared to those treated with concurrent chemotherapy/proton therapy. Differences in V5, V10 and V20 between patients treated with protons versus photons were also examined.

Materials and Methods

From 2002-2007 106 patients met the eligibility criteria for the present study. There were a total of 31 patients in the proton beam radiation arm (accrued from 2005-2007) and 75 patients in the IMRT arm (accrued from 2002-2007).

Eligibility Criteria:

All patients had to have histologically confirmed, locally advanced, non-small cell lung cancer. All patients had to be treated with concurrent chemotherapy, have had no prior thoracic radiation therapy, and have had received a total dose of greater than or equal to 60 cobalt gray equivalents (CGE). Patients who were treated with a combination of protons and photons, such as IMRT or 3D conformal radiation with protons, were excluded form this study. Additionally, patients treated with a combination of 3D conformal radiation and IMRT were excluded from this study. After 2004 all patients had radiation planning performed using 4D CT.

Toxicity:

The Common Terminology Criteria (CTC) for adverse events (version 3.0) was used to grade toxicity in patients. On this scale grade 3 represented symptomatic pneumonitis.

Chemotherapy: There were various regimens used in this study but the majority of patients received carboplatin and taxol with approximately 60% of patients in each arm receiving this regimen.

Results

The demographics, including gender, age and weight loss, were comparable between the two treatment groups. The chemotherapy used in each of the two treatment arms was not significantly different. The majority of patients had stage III disease. However, some patients with stage IIB and well controlled Stage IV disease were included in this study.

Median Follow up: For the proton arm median follow up was 9.5 months (range 1.6-16.1) as compared to 9.8 months (range 1.4-32.3) for the IMRT arm

Functional Status: The median KPS for both treatment arms was 80.

Median gross tumor volume (GTV): The median GTV for the IMRT arm was 247.7 cc (range 21-818) as compared to the proton arm where the median GTV was 93.6 cc (range 13-431) and this was significantly different (p<0.0001).

Shown are the V20’s for patients treated with protons versus photons stratified by tumor size. The rate of grade 3 pneumonitis stratified by tumor size is also shown.

Tumor Volume (cc)

Number of patients

V20

p-value

≥grade 2 pneumonitis

p-values

≤100

P=22

IMRT=9

21%

29%

0.124

2 (9.1%)

3 (33.3%)

0.10

≤200

P=28

IMRT=30

23%

30%

0.023

5 (17.9%)

10 (33.3%)

0.18

≤300

P=29

IMRT=43

24%

32%

0.002

5 (17.2%)

16 (37.2%)

0.07

≤400

P=30

IMRT=48

24%

32%

0.004

6 (20.0%)

19 (39.6%)

0.07

≤500

P=31

IMRT=56

24%

32%

0.007

6 (19.4%)

20 (35.7%)

0.11

Author's Conclusions

1) 9.3% of patients treated with IMRT developed grade 3 or higher pneumonitis compared to 0% of patients treated with proton therapy.

2) There was a trend towards decreased rates of pneumonitis as GTV increased in patients treated with protons as compared to patients treated with photons.

3) These preliminary results suggest that patients with locally advanced NSCLC treated with protons appeared to have lower rates of treatment related pneumonitis despite being treated to a higher dose.

4) Longer follow up is needed

5) The results of this study have served as the basis for a prospective trial which is currently accruing at MD Anderson comparing the use of concurrent proton/chemotherapy with IMRT/chemotherapy in patients with stage III lung cancer. The target goal for accrual in 168 patients.

Clinical/Scientific Implications

The risk of radiation pneumonitis greatly affects how radiation therapy is planned. The dose of radiation that the normal lung receives as well as the volume of normal lung irradiated plays an important role in determining the risk of pneumonitis. Prior studies have suggested that IMRT, due to its greater conformality can reduce the rate of penumonitis. Due to the ability to control the distal edge of the proton beam, the exit dose to normal tissue can be reduced. From the results of this study it appears that protons do reduce the volume of normal lung radiated and have the potential to decrease the rate of radiation penumonitis compared with IMRT. However, it is important to consider the condition of the “normal” lung prior to treatment and unfortunately there was no data on the pulmonary function of the patients. This study is retrospective and has a small number of patients which further limits the results. There was a large imbalance in GTV between the IMRT and proton arms as well and while they did stratify by GTV the number of patients in each stratum was relatively small.

It appears that all of the patients in the proton therapy group had 4D treatment planning while not all patients in the IMRT group did (4D planning was started in 2004) and this could have affect the analysis. Unfortunately, the small number of patients precluded a multivariate analysis.

There are also a number of problems that must be addressed when protons are used to treat lung cancer. Motion is a problem in proton treatment, as it is in photon therapy, however the range of the proton beam is also affected by the movement of tissues of different density (such as bone) into and out of the treatment field. This could result in under-dosing of the tumor or overdosing of normal structures. Furthermore, if the tumor responds and shrinks the conformality of the proton plan will be affected and rescanning with replanning may be needed. Weight change is also a frequent occurrence in patients with lung cancer who are on treatment and replanning may also be needed in cases of significant weight loss.

Nonetheless these results of this study are interesting and suggest that protons could reduce the risk of radiation pneumonitis and may allow further dose escalation, improving local control.